The proposed project will investigate metabolic, biosynthetic and membrane transport functions of erythroid precursor cells in sideroblastic anemia and erythroleukemia. It is our hypothesis that the characteristic disturbance in hemoglobin synthesis is due to an abnormality in the cellular uptake and transport of iron affecting in particular erythroid cells. Increased iron uptake will lead to excessive deposition in mitochondria thereby damaging metabolic and biosynthetic functions of this organelle and will stimulate the synthesis of ferritin which may compete with that of globin for available substrates. A comparative study of the energy metabolism and (lactic) acid production of erythroid precursors in these conditions offers a unique opportunity to test one of the current hypotheses of tumor growth, which stipulates that persistent alteration of intracellular pH leads to loss of regulatory mechanisms in the cell. Utilizing both suspensions and explants of bone marrow we shall examine in erythroid cells (purified by a combination of passage through glass wool columns and centrifugation through linear albumin gradients): 1) Uptake and transport of iron across plasma and mitochondrial membranes, 2) Rate of de novo synthesis of ferritin and hemoglobin, 3) Metabolic fate of deltaaminolevulinate and, 4) Energy metabolism. From these investigations we hope to define the pathogenetic mechanism of the disturbed hemoglobin synthesis and establish whether sideroblastic anemia and erythroleukemia are causually related. The therapeutic effectiveness of iron chelators and pyridoxine administration will also be assessed by in vitro experiments.